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Physiology of Aging Invited Review: Theories of Aging J Appl Physiol 95: 1706–1716, 2003; 10.1152/japplphysiol.00288.2003. highlighted topics Physiology of Aging Invited Review: Theories of aging Brian T. Weinert and Poala S. Timiras Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California 94720-3202 Weinert, Brian T. and Paola S. Timiras. Physiology of Aging. Invited Review: Theories of aging. J Appl Physiol 95: 1706–1716, 2003; 10.1152/japplphysiol.00288.2003.—Several factors (the lengthening of the average and, to a lesser extent, of the maximum human life span; the increase in percentage of elderly in the population and in the proportion of the national expenditure utilized by the elderly) have stimulated and continue to expand the study of aging. Recently, the view of aging as an extremely complex multifactorial process has replaced the earlier search for a distinct cause such as a single gene or the decline of a key body system. This minireview keeps in mind the multiplicity of mechanisms regulating aging; examines them at the molecular, cellular, and systemic levels; and explores the possibility of interactions at these three levels. The heterogeneity of the aging phenotype among individuals of the same species and differences in longevity among species underline the contri- bution of both genetic and environmental factors in shaping the life span. Thus, the presence of several trajectories of the life span, from incidence of disease and disability to absence of pathology and persistence of function, suggest that it is possible to experimentally (e.g., by calorie restriction) prolong functional plasticity and life span. In this minire- view, several theories are identified only briefly; a few (evolutionary, gene regulation, cellular senescence, free radical, and neuro-endocrine- immuno theories) are discussed in more detail, at molecular, cellular, and systemic levels. evolution; gene regulation; cellular senescence; free radical; neuro-endo- crine-immunologic regulation IN RECENT DECADES, THE STUDY of aging has expanded normal aging process alone or in combination with rapidly both in depth and in breadth. This growth has other theories. The definition of aging itself is open to been stimulated by 1) the extraordinary lengthening of various interpretations (14, 79). In response to the the average human life span, worldwide; 2) the less question “Why do we age?” aging is presented as an spectacular, but nevertheless significant, lengthening ontogenic issue; the process of growing old and/or the of the maximum life span; 3) the increasing percentage sum of all changes, physiological, genetic, molecular, of elderly in the population, especially in some devel- that occur with the passage of time, from fertilization oped countries; and 4) the increased proportion of the to death. In response to the question “Why do we live as national health expenditures utilized by the elderly long as we do?” an evolutionary-comparative frame- (96). Biological, epidemiologic, and demographic data work is the preferred address. To the question “Why do have generated a number of theories that attempt to we die?” the answer should underline the lack of nec- identify a cause or process to explain aging and its essary relation between aging (a definite period of the inevitable consequence, death. However, in recent life span) and death (an event that may occur at all years, the search for a single cause of aging, such as a ages). However, because aging is characterized by the single gene or the decline of a key body system, has declining ability to respond to stress and by increasing been replaced by the view of aging as an extremely homeostatic imbalance and incidence of pathology, complex, multifactorial process (43). Several processes death remains the ultimate consequence of aging. The- may interact simultaneously and may operate at many ories formulated to explain aging processes have been levels of functional organization (31). Similarly, differ- grouped into several categories, some of the most ent theories of aging are not mutually exclusive and widely used being the programmed and error theories may adequately describe some or all features of the of aging. According to the “programmed” theories, ag- ing depends on biological clocks regulating the timeta- ble of the life span through the stages of growth, Address for reprint requests and other correspondence: P. S. Timiras, Dept. of Molecular and Cell Biology, 401 Barker Hall, development, maturity, and old age: this regulation Berkeley, CA 94720-3202 (E-mail: [email protected]). would depend on genes sequentially switching on and 1706 8750-7587/03 $5.00 Copyright © 2003 the American Physiological Society http://www.jap.org INVITED REVIEW 1707 off signals to the nervous, endocrine, and immune radical reduction), cellular (e.g., mitochondrial protec- systems responsible for maintenance of homeostasis tion), and systemic (e.g., endocrine shifts) mechanisms and for activation of defense responses. The “error” (57). Although these interventions extend beyond the theories identify environmental insults to living organ- limits of the theories of aging themselves, they will be isms that induce progressive damage at various levels mentioned here in their support. Some of the principal (e.g., mitochondrial DNA damage, oxygen radicals ac- theories of aging to be discussed here are listed in cumulation, cross-linking). Table 1: several will be identified only briefly, whereas In the present review, we have categorized the var- a few will be discussed in detail. The latter include ious theories of aging as evolutionary, molecular, cel- evolutionary, gene regulation, cellular senescence, free lular, and systemic. The choice of these categories and radical, and neuro-endocrine-immuno theories. the order in which they are presented reflect their affinity to physiological discourse (90). Thus theories of EVOLUTIONARY THEORIES aging may overlap at various levels of organization: alterations with aging of molecular events may lead to Why do we live as long as we do? Evolutionary cellular alterations, and these, in turn, contribute to theories argue that aging results from a decline in the organ and systemic failure with evolutionary implica- force of natural selection. Because evolution acts pri- tions for reproduction and survival. In complex, multi- marily to maximize reproductive fitness in an individ- cellular organisms, the study of interactions among ual, longevity is a trait to be selected only if it is intrinsic (genetic), extrinsic (environmental), and sto- beneficial for fitness. Life span is, therefore, the result chastic (random damage to vital molecules) causes of selective pressures and may have a large degree of provides a fruitful approach conducive to a comprehen- plasticity within an individual species, as well as sive and realistic understanding of the aging process. among species. The evolutionary theory was first for- In humans, for example, the current longevity is the mulated in the 1940s based on the observation that result of an early (middle of last century) “epidemio- Huntington’s disease, a dominant lethal mutation, re- logic transition,” referring to the decline in death rates mained in the population even though it should be due to acute infectious disease (because of improved strongly selected against (34). The late age of onset for hygiene and the discovery of antibiotics) (101). This Huntington’s disease (30–40 yr) allows a carrier to was followed in the 1970s to 1980s by a second mortal- reproduce before dying, thereby allowing the disease to ity decline at older ages in the reduction of death rates avoid the force of natural selection. This observation due to cardiovascular disease (101). In several animal inspired the Mutation Accumulation Theory of aging, species (rodents, monkeys), experimental interven- which suggests that detrimental, late-acting mutations tions such as restriction of dietary calories show that it may accumulate in the population and ultimately lead is possible to delay the onset of pathology and to pro- to pathology and senescence (59). Currently, there is long the life span by manipulating molecular (e.g., free scant experimental evidence for this theory of aging (67). Table 1. Classification and brief description of main theories of aging Biological Level/Theory Description Evolutionary Mutation accumulation* Mutations that affect health at older ages are not selected against. Disposable soma* Somatic cells are maintained only to ensure continued reproductive success; after reproduction, soma becomes disposable. Antagonistic pleiotropy* Genes beneficial at younger age become deleterious at older ages. Molecular Gene regulation* Aging is caused by changes in the expression of genes regulating both development and aging. Codon restriction Fidelity/accuracy of mRNA translation is impaired due to inability to decode codons in mRNA. Error catastrophe Decline in fidelity of gene expression with aging results in increased fraction of abnormal proteins. Somatic mutation Molecular damage accumulates, primarily to DNA/genetic material. Dysdifferentiation Gradual accumulation of random molecular damage impairs regulation of gene expression. Cellular Cellular senescence-Telomere theory* Phenotypes of aging are caused by an increase in frequency of senescent cells. Senescence may result from telomere loss (replicative senescence) or cell stress (cellular senescence). Free radical* Oxidative metabolism produces highly reactive free radicals that subsequently damage lipids,
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